Director's Report to the National Advisory Council on Drug Abuse - September, 2005

Research Findings - Clinical Neuroscience Research

Recognition and Management of Complications of New Recreational Drug Use

Social use of illicit drugs in clubs and large dance parties (i.e., raves) is an escalating cultural trend. Such recreational drug use is associated with several medical complications, both acute and chronic. Although few, if any, of the drugs currently used in recreational situations are truly new, their patterns and context of use have changed (substantially in some instances). For some of these substances, a cultural repackaging of the drug experience has resulted in various medical disorders that have previously gone undocumented. This review by Hopkins researchers aims to help treating physicians recognize and manage complications associated with the use of new drugs in clubs, including methylenedioxy-methamphetamine, ephedrine, gamma-hydroxybutyrate, gamma-butyrolactone, 1,4-butanediol, flunitrazepam, ketamine, and nitrites. The article also alerts researchers to specific toxic effects of club-drugs on which more basic information is needed. Ricaurte, G.A. and McCann, U.D. Lancet, 7, pp. 2137-2145, 2005.

Interaction of Executive Functions, Sensation Seeking, and HIV Serostatus and its Effect on the Risky Sexual Practices of Drug Abusers

From a public health standpoint, identifying factors that contribute to risky sexual practices among substance-dependent individuals is critical, particularly in the context of HIV infection. Investigators from the University of Illinois, Chicago, examined the contributions of executive neurocognitive functions, sensation seeking, and HIV serostatus to predict risky sexual practices among poly-substance abusers with a history of cocaine or cocaine/heroin (speedballing). HIV+ (n=109) and HIV- (n=154) substance-dependent individuals were assessed using three neurocognitive tasks of executive functions: Stroop reaction time, delayed non-matching to sample, and the Iowa Gambling Task. Sensation seeking was assessed using the Sensation Seeking Scale-V. Greater sensation seeking was associated with more risky sexual practices among HIV+ participants, particularly among those who performed best on the Iowa Gambling Task. The findings indicate that continued risk behavior among HIV+ drug users may be driven by sensation seeking (a personality trait common among drug users); however, the impact of executive functions is less clear. Gonzalez, R., Vassileva, J., Bechara, A., Grbesic, S., Sworowski, L., Novak, R.M., Nunnally, G. and Martin, E.M. J. International Neuropsychological Society 11, pp. 121-131, 2005.

It is known that chronic methamphetamine (METH) abuse is associated with cerebral deficits, involving frontal/basal-ganglia regions that are important for inhibitory control. Researchers from UCLA used the Stop-Signal Task to measure response inhibition in 11 abstinent METH abusers (5-7 days abstinent) and two groups of control subjects who did not use METH (14 tobacco smokers and 29 non-smokers). Stop-signal reaction time (SSRT), which indicates the latency to inhibit an initiated motor response, was significantly longer for METH abusers than for either control group. In contrast, the METH abusers did not differ from either group on Go trial reaction time (RT) or number of discrimination errors, which reflect motor speed and decision-processes, respectively. In this study, METH abuse was therefore associated with a specific deficit in inhibiting a pre-potent response. The authors speculate that future research could examine whether SSRT is different for METH abusers who respond to treatment compared to those who do not. If such differences are established then response inhibition may serve as a marker for investigating METH abuse in basic science and clinical trials. Monterosso, J.R., Aron, A.R., Cordova, X., Xu, J. and London, E.D. Drug Alcohol Depend.79, pp. 273-277, 2005.

Repeated Psychological Stress Testing in Stimulant-Dependent Patients

Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine (COC)- or methamphetamine (METH)-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. COC users and METH users did not respond similarly in their craving responses. Reported craving for METH after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response. Harris, D.S., Reus, V.I., Wolkowitz, O.M., Mendelson, J.E. and Jones R.T. Prog Neuropsychopharmacol Biol Psychiatry 29, pp. 669-677, 2005.

Imaging Brain Mu-Opioid Receptors in Abstinent Cocaine Users Over Time and in Relation to Craving

Cocaine (coc) treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. These researchers have previously used positron emission tomography (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 coc-dependent men after 1 and 28 days of abstinence. Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 coc users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects. Results demonstrate that mOR BP was increased in the frontal, AC, and LTC after 1 day of abstinence. mOR BP remained elevated in the first two regions after 1 week and in the AC and AFC after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. mOR BP was significantly correlated with percentage of days coc was used and the amount of coc used per day during the 2 weeks prior to admission and with urine benzoylecgonine concentration at the first PET scan. These results suggest that chronic coc use influences endogenous opioid systems in the human brain and might explain mechanisms of coc craving and reinforcement. Gorelick, D.A., Kim, Y.K., Bencherif, B., Boyd, S.J., Nelson, R., Copersino, M., Endres, C.J., Dannals, R.F. and Frost, J.J. Biological Psychiatry, 15, pp. 573-582, 2005.

When smokers who are nicotine-dependent abstain from cigarette smoking, working memory deficits occur. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. The aim of researchers at UCLA, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from smoking. BOLD fMRI was used to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (=1.5 hours abstinence) and abstinence (>/=14 hours abstinence) conditions. Task-related activity in the DLPFC showed a significant interaction between test session (satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected that task-related activity in the satiety condition was relatively low during performance of the 1-back task but greater at the more difficult task levels, whereas task-related activity in the abstinence condition was relatively high at the 1-back level and did not increase at the more difficult task levels. It is concluded that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety. Xu, J., Mendrek, A., Cohen, M.S, Monterosso, J., Rodriguez, P., Simon, S.L., Brody, A., Jarvik, M., Domier, C.P., Olmstead, R., Ernest, M. and London, E. Biological Psychiatry. 15, pp. 143-150, 2005.

Researchers from UCLA examined the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. It is concluded that HCV infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations. Cherner, M., Letendre, S., Heaton, R.K., Durelle, J., Marquie-Beck, J., Gragg, B., Grant, I. and HIV Neurobehavioral Research Center Group. Neurology, 26, pp. 1343-1347, 2005.

Effects of Methamphetamine Dependence and HIV Infection on Cerebral Morphology

Researchers at UCLA examined the separate and combined effects of methamphetamine dependence and HIV infection on brain morphology. Morphometric measures obtained from magnetic resonance imaging of methamphetamine-dependent and/or HIV+ participants and their appropriate age- and education-matched comparison groups were analyzed. Main effects of age, HIV infection, METH dependence, and the interactions of these factors were examined in analyses of cerebral gray matter structure volumes. Independent of the effect of age, HIV infection was associated with reduced volumes of cortical, limbic, and striatal structures. There was also some evidence of an interaction between age and HIV infection such that older HIV+ participants suffered disproportionate loss. METH dependence was surprisingly associated with basal ganglia and parietal cortex volume increases, and in the nucleus accumbens there appeared to be a larger effect in younger methamphetamine abusers. Neurocognitive impairment was associated with decreased cortical volumes in HIV+ participants but with increased cortical volumes in METH-dependent participants. Results suggest significant brain structure alterations associated with both HIV infection and METH. The regional patterns of the changes associated with these factors were distinct but overlapping, and the effects on brain volumes were opposing. Although the results of the present study provide little information about the specific mechanisms leading to the unexpected methamphetamine effects, they may be related to glial activation or neuritic growth, both of which have been associated with methamphetamine exposure in animal studies. The findings have implications for the interpretation of brain morphological findings in METH+/HIV+ individuals, a group whose numbers are unfortunately increasing. Jernigan, T.L., Gamst, A.C., Archibald, S.L., Fennema-Notestine, C., Mindt, M.R., Marcotte, T.L., Heaton, R.K., Ellis, R.J. and Grant, I. American Journal of Psychiatry, 162, pp. 1461-1472, 2005.

Sleep Quality Deteriorates In Two Weeks Following Abstinence From Smoked Cocaine

Stickgold, Hobson and associates at Harvard found that sleep quality - duration, efficiency, and onset latency, but not subjective report - deteriorated over 15 days following abstinence from a binge session of smoked cocaine. The subjects were non-treatment-seeking cocaine abusers who participated in an inpatient study of binge use followed by two-week abstinence. Polysomnography assessed sleep quality and confirmed a steadily decreasing sleep quality, phenomena reported by others. There was not, however, evidence of REM rebound that has been reported by other studies which may be due to the hospital setting in this study or other factors. The main limitation in this study was the small number of subjects (though more than other studies), requiring replication. Nevertheless, sleep disturbances are likely one source of relapse in those trying to quit. Pace-Schott, E.F., Stickgold, R., Muzur, A., Wigren, P.E., Ward, A.S., Hart, C.L, Clarke, D., Morgan, A. and Hobson J.A.. Psychopharmacology 179, pp. 873-883, 2005.

Significant Association of the _4 Subunit of the Nicotine Acetylcholine Receptor with Nicotine Dependence

M.D. Li and colleagues studied over 2000 subjects from more than 600 families with three measures of smoking severity (heaviness, quantity, and dependence) and demonstrated association with at least two (of six studied) single nucleotide polymorphisms (SNPs). However, different SNPs were associated in different ethnic groups (African Americans and European Americans). Furthermore, in female African Americans on SNP was significantly associated with all three nicotine dependence measures. The _2 subunit of the nACHR gene was also examined but no association was found. This study is believed to be the first to confirm a genetic role of the CHRNA4 gene, separately in African and European American samples as well as indicate that such an association may be sex-specific as well. Li, M.D., Beuten, J., Ma, J.Z., Payne, T.J., Lou, X.-Y., Garcia, V., Duenes, A.S., Crews, K.M. and Elston, R.C. Human Molecular Genetics, 14, pp. 1211-1219, 2005.

Genetic Linkages For Cocaine Dependence and Related Traits

Gelernter at Yale University and associates reported significant linkage (lod score = 4.66) for an empirically-derived symptom cluster entitled, "Heavy use, cocaine predominant," at position 104.7 on Chromosome 12 for European Americans only. For African Americans there was a significant peak at 52.9 on Chromosome 3 for the cluster entitled, "Moderate cocaine and opiate use." Two suggestive peaks (lod ~2.5) were found for European Americans for cocaine dependence and for "Heavy use, cocaine predominant" at 52.9 on Chromosome 3. For African Americans for whom cocaine induced paranoia (CIP), there was a significant peak (lod = 3.65) at location 117.4 on Chromosome 9. These data demonstrate differences in genotype vulnerabilities among ethnic groups while pointing to chromosomal regions for further study into the genetic basis of drug abuse vulnerability. Gelernter, J., Panhuysen, C., Weiss, R., Brady, K., Hesselbrock, V. Rounsaville, B., Poling, J., Wilcox, M., Farrer, L. and Kranzler, H.R. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 136B, pp. 45-52, 2005.

Gelernter at Yale University and associates studied six markers and 38 ancestry-informative markers in a sample of 871 subjects including controls and individuals with diagnoses of drug dependence, alcohol dependence and/or major depressive syndrome. Using a conventional case-control design some of the markers were marginally significant which did not hold up when corrected for multiple testing. However, regression analysis did identify specific alleles, genotypes, and haplotypes that were associated with risk for each disorder. The authors concluded that variation in the cholinergic muscarinic receptor predisposes to the disorders under investigation. Allele interaction demonstrated increased risk for alcohol and drug dependence while not for affective disorders indicating counteracting forces. Luo, X., Kranzler, H.R., Zuo, L., Wang, S., Blumberg, H.P. and Gelernter, J. HMG Advance Access, July 2005.

Increased DAT Availability Associated With 9-Repeat of the SLC6A3 Gene

Gelernter and associates at Yale University determined that homozygotes with 9 repeats of a 40-base-pair segment in the 3' untranslated region of the SLC6A3 gene together with heterozygotes (with a 10-repeat segment) compared to 10-repeat homozygotes had less dopamine transporter available in both the caudate and putamen when corrected for age and as determined by SPECT. In addition there was a left/right asymmetry with more availability in the left putamen and (marginally) caudate. These data replicate a previous study by these investigators but differ from others with possible differences due to diagnosis, methodology, or ethnic composition. The repeat is not in the coding region rendering the cause for the differences to be unknown-possibly affecting gene expression, being in linkage equilibrium with another gene variant, or related to other polymorphism as yet unknown. Van Dyck, C.H., Malison, R.T., Jacobsen, L.K., Sebyl, J.P., Staley, J.K., Laruell, M., Baldwin, R.M., Innis, R.B. and Gelernter, J. Journal of Nuclear Medicine, 46, pp. 745-751, 2005.

fMRI Brain Activation during Cocaine Self-Administration in Humans

Risinger and colleagues at the Medical College of Wisconsin used BOLD fMRI to determine pattern of brain activation during cocaine self-administration in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often to administer i.v. cocaine within a medically supervised self-administration procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h self-administration period. Drug-induced HIGH was found to correlate negatively with activity, in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system. Risinger, R.C., Salmeron, B.J., Ross, T.J., Amen, S.L., Sanfilipo, M., Hoffmann, R.G., Bloom, A.S., Garavan, H. and Stein, E.A. Neuroimage 26, pp. 1097-1108, 2005.

Paulus and colleagues at the University of California, San Diego investigated whether BOLD functional magnetic resonance imaging (fMRI) shortly after drug cessation could predict relapse in stimulant-dependent individuals. Treatment-seeking methamphetamine-dependent males (N = 46) were scanned using fMRI while performing a 2 choice prediction task 3 to 4 weeks after cessation of drug use. Of the 40 subjects who were followed up a median of 370 days, 18 relapsed and 22 did not. fMRI activation patterns in right insular, posterior cingulate, and temporal cortex obtained early in recovery correctly predicted 20 of 22 subjects who did not relapse and 17 of 18 subjects who did. A Cox regression analysis revealed that the combination of right middle frontal gyrus, middle temporal gyrus, and posterior cingulate activation best predicted the time to relapse. In contrast, behavioral performance on the task was not predictive of relapse. This investigation demonstrates that fMRI can be used to predict relapse in substance-dependent individuals. Paulus, M.P., Tapert, S.F. and Schuckit, M.A. Archives of General Psychiatry 62, pp. 761-768, 2005.

Nordahl and colleagues at the University of California, Davis measured cerebral metabolite levels using magnetic resonance spectroscopy imaging techniques in early abstinent vs long term (at least one year) methamphetamine users and healthy controls. MRS measured N-acetylaspartate-creatine and phosphocreatine (NAA/Cr), choline-creatine and phosphocreatine (Cho/Cr), and choline-N-acetylaspartate (Cho/NAA) ratios were obtained in the anterior cingulate cortex as well as in the primary visual cortex, which served as a control region. The absolute values of Cr did not differ between controls and methamphetamine users. Methamphetamine users had abnormally low NAA/Cr levels within the anterior cingulate cortex, regardless of the time spent abstinent. No NAA/Cr group differences were observed in the primary visual cortex (F(2,33) = 0.29; P = .75). The Cho/NAA values for the anterior cingulate cortex were abnormally high in the methamphetamine users who recently initiated abstinence were at normal levels in long-term abstinent methamphetamine users. Results are consistent with adaptive changes following cessation of methamphetamine use in the anterior cingulate. Nordahl, T.E, Salo, R., Natsuaki, Y., Galloway, G.P., Waters, C., Moore, C.D., Kile, S. and Buonocore, M.H. Archives of General Psychiatry 62, pp. 444-452, 2005.

Lack of Hippocampal Volume Change in Long-Term Heavy Cannabis Users

Yurgelun-Todd and colleagues at McLean Hospital used structural MRI to investigate the effect of chronic cannabis smoking on the morphology of the hippocampus. Structural MRI was performed on 22 older, long-term cannabis users (reported a mean [SD] of 20,100 [13,900] lifetime episodes of smoking) and 26 comparison subjects with no history of cannabis abuse or dependence. When compared to control subjects, smokers displayed no significant adjusted differences in volumes of gray matter, white matter, cerebrospinal fluid, or left and right hippocampus. Moreover, hippocampal volume in cannabis users was not associated with age of onset of use nor total lifetime episodes of use. These findings are consistent with recent literature suggesting that cannabis use is not associated with structural changes within the brain as a whole or the hippocampus in particular. Tzilos, G.K., Cintron, C.B., Wood, J.B.R., Simpson, N.S., Young, A.D., Pope, H.G. and Yurgelun-Todd, D.A. American Journal on Addictions 14, pp. 64-72, 2005.

Cognitive Impairment in Acute Cocaine Withdrawal

Beversdorf and colleagues at Ohio State University investigated whether in human substance abusers early in cocaine withdrawal there are impairments in a range of cognitive flexibility tasks known to be sensitive to changes in noradrenergic tone. Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence-matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention. As predicted, impairments were found on the cognitive flexibility tasks, especially in the Anagram Generation task. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention. These results suggest that cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic network. These results are consistent with studies showing treatment benefits for propranolol patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response. Kelley, B.J., Yeager, K.R., Pepper, T.H. and Beversdorf, D.Q. Cognitive and Behavioral Neurology 18, pp. 108-112, 2005.

Shape Changes of the Corpus Callosum in Abstinent Methamphetamine Users

Renshaw and colleagues at McLean Hospital used structural MRI to evaluate structural changes of the corpus callosum (CC) in abstinent methamphetamine (MA) users. Shape and size of the CC in 27 MA users were compared to those of 18 healthy comparison subjects. To define the local curvature and width of the CC, medial model-based shape analysis was performed using CC skeletons extracted from 41-distance map. To define the local displacement of the CC, a boundary model-based shape analysis was performed. In addition, the size of regional areas of the CC was measured. In the medial model-based shape analysis, increased curvature in the genu (curvature angle difference=4.1') and decreased width in posterior midbody (width difference=0.77 mm) and isthmus area (width difference=0.86 mm) of the CC were observed in MA users relative to healthy comparison subjects. In the boundary model-based shape analysis, significant displacement was observed in MA users where there were differences in shape/width patterns by the medial model-based shape analysis. There were no differences in the size of regional areas of the CC between groups. Findings suggest that MA use is associated with regional changes in interhemispheric white matter tracts, which connect frontal and parietal cortices and that these frontal and parietal abnormalities may underlie clinical manifestations of MA abuse. Oh, J.S., Lyoo, I.K., Sung, Y.H., Hwang, J., Kim, J., Chung, A., Park, K.S., Kim, S.J., Renshaw, P.F. and Song, I.C. Neuroscience Letters 384, pp. 76-81, 2005.

Bechara and colleagues at the University of Iowa used a laboratory task to determine whether chronic use of MDMA and THC can impair cognitive processes that help direct our safe movement, and therefore can increase the risk of driving accidents. The study participants were grouped according to their drug use history into 2 groups: MDMA/THC user, and users of THC alone. Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles. On each trial, subjects reported if direction of travel was to the left or the right. Results showed impairments in both drug groups, with the MDMA/THC group performing the worst. The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability. Rizzo, M., Lamers, C.T., Sauer, C.G., Ramaekers, J.G., Bechara, A. and Andersen, G.J. Psychopharmacology 179, pp. 559-566, 2005.

Increased Risk-Taking Decision-Making But Not Altered Response to Punishment in Stimulant-Using Young Adults

Paulus and colleagues at the University of California, San Diego investigated whether increased risky behavior is evident in stimulant-na•ve subjects. Stimulant-using (but not dependent) young adults non-stimulant using subject performed a "risky gains" decision-making task. On each trial, the numbers 20, 40, and 80 are presented individually in ascending order. Subjects press a button to receive the displayed number in points. The 20 is always associated with a gain of 20 points (safe response). There is a chance that waiting to select a 40 or 80 will result in punishment of 40 or 80 points, respectively (risky response). All subjects made fewer risky responses immediately following punished trials (p

Zubieta, Domino and colleagues at the University of Michigan used PET to determine the effects of cigarette smoking on brain regional function in a group of chronic smokers on cerebral blood flow (CBF). Nineteen tobacco smokers were studied after about 12 hours of smoking abstinence. Regional CBF (rCBF) measures were obtained with PET and [O-15] H2O in six consecutive scans. Two average-nicotine-yield (1.0 mg) and one denicotinized (0.08 mg) research cigarettes with similar tar yields (9.5 mg and 9.1 mg, respectively) were smoked in a double-blind design, preceded and followed by baseline scans. The rCBF effects of smoking were compared to baseline measures and between cigarettes, as well as to subjective ratings of craving for cigarettes. Smoking the first cigarette of the day resulted in increases in rCBF in the visual cortex and the cerebellum and reductions in the anterior cingulate, the right hippocampus, and the ventral striatum, including the nucleus accumbens. Cigarette craving scores correlated with rCBF changes in the dorsal anterior cingulate and right hippocampus. Less pronounced effects were observed with the second cigarette and the denicotinized cigarette. Smoking affects rCBF not only in areas of the brain rich in nicotinic cholinergic receptors but also in areas implicated in the rewarding effects of drugs of abuse. Furthermore, craving for a cigarette in chronic smokers was correlated with rCBF in the right hippocampus, an area involved in associating environmental cues with drugs, and in the left dorsal anterior cingulate, an area implicated in drug craving and relapse to drug-seeking behavior. Zubieta, J.K., Heitzeg, M.M., Xu, Y..J, Koeppe, R.A., Ni, L.S., Guthrie, S. and Domino, E.F. American Journal of Psychiatry 162, pp. 567-577, 2005.

Dissociation of Inhibition from Error Processing Using a Parametric Inhibitory Task During Functional Magnetic Resonance Imaging

Paulus and colleages at the University of California, San Diego used fMRI to investigate brain activation patterns involved in inhibition, the process that overrides and reverses the execution of a thought, action, or emotion, and is important in daily life. Sixteen healthy volunteers performed a parametrically modulated motor inhibition task during functional magnetic resonance imaging. Two results were observed: (1) increased error-related anterior cingulate cortex activation and, (2) increased inferior frontal gyrus and medial prefrontal cortex activation during inhibition, irrespective of errors. Thus, the parametric nature of the task elucidated a functional dissociation of brain structures involved in motor inhibition from those involved in error processing. Additionally, this task allowed the identification of unique areas of increased activation within specific subregions of the anterior cingulate cortex related to errors made during trials with a high (dorsal anterior cingulate cortex) and low (ventral anterior cingulate cortex) inhibitory load. Matthews, S.C., Simmons, A.N., Arce, E. and Paulus M.P. Neuroreport 16, pp. 755-760, 2005.

Investment Behavior And The Negative Side Of Emotion

Bechara and colleagues at the University of Iowa investigated whether dysfunction in neural systems subserving emotion can lead, under certain circumstances, to more advantageous decisions. In this study normal participants, patients with stable focal lesions in brain regions related to emotion (target patients), and patients with stable focal lesions in brain regions unrelated to emotion (control patients) made 20 rounds of investment decisions. Target patients made more advantageous decisions and ultimately earned more money from their investments than the normal participants and control patients. When normal participants and control patients either won or lost money on an investment round, they adopted a conservative strategy and became more reluctant to invest on the subsequent round, these results suggest that they were more affected than target patients by the outcomes of decisions made in the previous rounds. These results suggest that brain dysfunction may paradoxically result in improved performance in decision-making tasks under certain conditions. Shiv, B., Loewenstein, G., Bechara, A., Damasio, H. and Damasio, A.R. Psychological Science 16, pp. 435-439, 2005.

Huettel and colleagues at Duke University used BOLD fMRI to investigate patterns of brain activity when decisions are made under uncertainty, that is, with limited information about their potential consequences. Previous neuroimaging studies of decision-making have implicated regions of the medial frontal lobe in processes related to the resolution of uncertainty. However, a different set of regions in dorsal prefrontal and posterior parietal cortices has been reported to be critical for selection of actions to unexpected or unpredicted stimuli within a sequence. In the current study, authors induced uncertainty using a novel task that required subjects to base their decisions on a binary sequence of eight stimuli so that uncertainty changed dynamically over time (from 20 to 50%), depending on which stimuli were presented. Activation within prefrontal, parietal, and insular cortices increased with increasing uncertainty. In contrast, within medial frontal regions, as well as motor and visual cortices, activation did not increase with increasing uncertainty. Authors conclude that the brain response to uncertainty depends on the demands of the experimental task. When uncertainty depends on learned associations between stimuli and responses, as in previous studies, it modulates activation in the medial frontal lobes. However, when uncertainty develops over short time scales as information is accumulated toward a decision, dorsal prefrontal and posterior parietal contributions are critical for its resolution. The distinction between neural mechanisms subserving different forms of uncertainty resolution provides an important constraint for neuroeconomic models of decision-making. These results also may aid the interpretation of recent studies showing anatomical changes in parietal cortical structures and activation in methamphetamine users. Huettel, S.A., Song, A.W. and McCarthy, G. Journal of Neuroscience 25, pp. 3304-3311, 2005.

Superior Temporal Gyrus and Insula Provide Response and Outcome-Dependent Information During Assessment and Action Selection in a Decision-Making Situation

Paulus and colleagues at the University of California, San Diego used BOLD fMRI to investigate whether distinct neural systems may contribute differentially during various stages within a decision-making situation. This study investigated whether neural activation during assessment or action selection is critically dependent on previous outcomes or actions. Twelve healthy, right-handed subjects (6 females) played a Rock Paper Scissors (RPS) computer game during functional magnetic resonance imaging. Bilateral insula and medial prefrontal cortex (including the anterior cingulate) were specifically engaged during the assessment and action selection stages of decision-making, whereas bilateral superior frontal gyrus and right inferior parietal lobule activated more during the outcome. Two regions of activation within the bilateral superior temporal gyrus activated only when the previous outcome was a win. Moreover, right insula and superior temporal gyrus were active more when the subject switched responses relative to staying with the same choice made on the previous trial. These findings support the hypothesis that distinct neural systems underlie different stages of the decision-making process. Furthermore, the superior temporal gyrus may play an important role in integrating previous actions and successful outcomes into one's decision-making strategy. These results may be directly related to recent findings by the same investigators that decreased activation in these regions predict relapse in methamphetamine abusers. Paulus, M.P., Feinstein, J.S., Leland, D. and Simmons, A.N. Neuroimage 25, pp. 607-615, 2005.

Yurgelun-Todd and colleagues at McLean Hopsital used BOLD fMRI to investigate the relationship between weight status and reward-related brain activity in normal weight humans. Orbitofrontal and anterior cingulate cortex activity as measured by fMRI in 13 healthy, normal-weight adult women as they viewed images of high-calorie and low-calorie foods, and dining-related utensils. Body mass index correlated negatively with both cingulate and orbitofrontal activity during high-calorie viewing, negatively with orbitofrontal activity during low-calorie viewing, and positively with orbitofrontal activity during presentations of nonedible utensils. With greater body mass, activity was reduced in brain regions important for evaluating and modifying learned stimulus-reward associations, suggesting a relationship between weight status and responsiveness of the orbitofrontal cortex to rewarding food images. Killgore, W.D.S. and Yurgelun-Todd, D.A. Neuroreport 16, pp. 859-863, 2005.

Electrophysiological Correlates of Reward Prediction Error Recorded in the Human Prefrontal Cortex

Bechara and colleagues at the University of Iowa investigated used electrophysiological recordings to directly determine neuronal activity in the ventral medial prefrontal cortex during risky behavior. They recording directly from prefrontal depth electrodes in a rare neurosurgical patient while he performed the Iowa Gambling Task, and concurrently measured behavioral, autonomic, and electrophysiological responses. Authors found a robust alpha-band component of event-related potentials that reflected the mismatch between expected outcomes and actual outcomes in the task, correlating closely with the reward-related error obtained from a reinforcement learning model of the patient's choice behavior. The finding implicates this brain region in the acquisition of choice bias by means of a continuous updating of expectations about reward and punishment. Oya, H., Adolphs, R., Kawasaki, H., Bechara, A., Damasio, A. and Howard, M.A. Proceedings National Academy of Sciences, USA 102, pp. 8351-8356, 2005.

Emotion-Modulated Performance and Activity in left Dorsolateral Prefrontal Cortex

Miller and colleagues at the University of Illinois used BOLD functional MRI (fMRI) to examine the relationship between processing of pleasant and unpleasant stimuli and activity in prefrontal cortex in normal healthy subjects. Twenty volunteers identified the colors in which pleasant, neutral, and unpleasant words were printed, Pleasant words prompted more activity bilaterally in dorsolateral prefrontal cortex (DLPFC) than did unpleasant words, In addition, pleasant words prompted more activity in left than in right DLPFC. Response speed to pleasant words was correlated with DLPFC activity. These data directly link positive affect to enhanced prefrontal activity, providing some of the first fMRI evidence supporting models of emotional valence and frontal brain asymmetry based on electroencephalography (EEG). Herrington, J.D., Mohanty, A., Koven, N.S., Fisher, J.E., Stewart, J.L., Banich, M.T., Webb, A.G, Miller, G.A. and Heller, W. Emotion 5(2), pp. 200-207, 2005.

Reinstatement of Conditioned Fear in Humans Is Context Dependent and Impaired in Amnesia

LaBar and Phelps at New York University used a contextual reinstatement procedure to assess the contributions of environmental cues and hippocampal function in the recovery of conditioned fear following extinction in humans. They showed context specificity in the recovery of extinguished skin conductance responses after presentations of an auditory unconditioned stimulus, and that fear recovery did not generalize to an explicitly impaired conditioned stimulus. In addition, the context dependency of fear recovery was replicated using a shock as an unconditioned stimulus. Two amnesic patients failed to recover fear responses following reinstatement in the same context, despite showing initial fear acquisition. These results extend the known functions of the human hippocampus and highlight the importance of environmental contexts in regulating the expression of latent fear associations. LaBar, K.S. and Phelps, E.A. Behavioral Neuroscience 119, pp. 677-686, 2005.

fMRI Sensitization to Angry Faces

Breiter and colleagues used BOLD fMRI to map the neural substrates of responses to facial expressions of anger and evaluated the motivational salience of these stimuli. During functional magnetic resonance imaging, angry and neutral faces were presented to human subjects. Across experimental runs, signal adaptation was observed. Whereas fearful faces have reproducibly evoked response habituation in amygdala and prefrontal cortex, angry faces evoked sensitization in the insula, cingulate, thalamus, basal ganglia, and hippocampus. Complementary offline rating and key-press experiments determined an aversive rank ordering of angry, fearful, neutral, and happy faces and revealed behavioral sensitization to the angry faces. Subjects rated angry faces, in contrast to other face categories such as fear, as significantly more likely to directly inflict harm. Furthermore, they rated angry faces as significantly less likely to produce positive emotional outcomes than the other face categories. Together these data argue that angry faces, a directly aversive stimulus, produce a sensitization response. These studies form the basis for studying whether drug abusers have altered responses to social stimuli. Strauss, M.M., Makris, N., Aharon, I., Vangel, M.G., Goodman, J., Kennedy, D.N., Gaslc, G.P. and Breiter, H.C. Neuroimage 26, pp. 389-413, 2005.